Comparative analysis of the targetable landscape in <i>KRAS</i>-mutant and wild-type pancreatic adenocarcinoma.
Authors: Todd C Knepper, Dae Won Kim, Elizabeth Mauer, Karyn Ronski, Pat Gulhati
Journal: Journal of Clinical Oncology (2022)

4155 Background: Pancreatic adenocarcinoma (PC) is the fourth leading cause of cancer deaths, with increased incidence among patients (pts) younger than 50 years old (yo). Small cohort studies suggest early-onset PC (EOPC, diagnosis at &lt; 50 yo) tumors may have a unique biology, harboring a higher proportion of KRAS wild-type status ( KRAS WT ) and enrichment of targetable mutations/fusions compared to non-EOPC. In addition, therapy targeting oncogenic fusions in KRAS WT tumors has shown meaningful responses in PC pts. Here, we investigate the prevalence of fusions, mutations, and homologous recombination deficiency (HRD) in KRAS WT PC to identify potential targets for therapeutic intervention, and compare EOPC to non-EOPC to better characterize EOPC differences. Methods: De-identified records from 4,956 PC pts with tumor biopsies sequenced using the Tempus xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq) were retrospectively reviewed. Fusions were detected from RNA-seq data via the Tempus bioinformatics pipeline. Mutations identified included germline and/or somatic single-nucleotide variants and insertions/deletions. HRD status was determined from RNA-seq data by the Tempus HRD test. Significance was determined as FDR-corrected p-values &lt; 0.05. Results: Across the entire cohort, 21% tumors were KRAS WT . HRD was more frequent in KRAS WT (7.9%) compared to KRAS MUT (3.1%) tumors ( P&lt; 0.001). Significant somatic mutational differences between the KRAS WT and KRAS MUT cohorts included BRAF (5.0% vs 0.2%) , CDKN2A (5.4% vs 25%), ARID1A (3.6% vs 8.6%), CTNNB1 (1.3% vs 0.3%), and TSC2 (1.2% vs 0.1%) (all P&lt; 0.001). Actionable rearrangements were enriched in the KRAS WT cohort (10% vs 2.1%, P&lt; 0.001); the most common fusion partners include NRG1, MET, RAF1, BRAF, NTRK1-3, FGFR 1-4, and RET. TMB-high (10 muts/Mb) and MSI-high were more common in KRAS WT (2.9% and 1.0%) compared to KRAS MUT (1.7% and 0.4%) tumors ( P= 0.015). Additionally, 382 pts were classified as EOPC. KRAS WT tumors comprised 30% of EOPCs, 22% of the 50-70 yo cohort, and 17% of the &gt; 70 yo cohort. Germline (pathogenic/likely pathogenic) alterations in BRCA1 and BRCA2 were more frequent in EOPCs (2.0% and 4.5%) compared to the 50-70 yo (0.4% and 1.7%) and &gt; 70 yo (0.4% and 0.8%) cohorts ( P= 0.015 and &lt; 0.001, for BRCA1 and BRCA2 respectively). There were no statistical differences in actionable genes detected in EOPC vs non-EOPC. HRD was found at higher frequency in EOPC (5.4%) and decreased in age cohorts 50-70 yo (4.7%) and &gt; 70 yo (2.5%) ( P = 0.047). Rearrangements were more common in EOPC compared to non-EOPC (10% vs 1.1%, P&lt; 0.001). Conclusions: HRD, TMB-H/MSI-H and oncogenic rearrangements are more prevalent in KRAS WT PC when compared with KRAS MUT . These molecular analyses may provide additional therapeutic options for PC pts, warranting comprehensive genomic and transcriptomic profiling for this population.